Schistosome-Associated Pulmonary Arterial Hypertension: A Review Emphasizing Pathogenesis

Abstract

Schistosomiasis, especially due to Schistosoma mansoni, is a well-recognized cause of pulmonary arterial hypertension (PAH). The high prevalence of this helminthiasis makes schistosome-related PAH (Sch-PAH) one of the most common causes of this disorder worldwide. The pathogenic mechanisms underlying Sch-PAH remain largely unknown. Available evidence suggests that schistosome eggs reach the lung via portocaval shunts formed as a consequence of portal hypertension due to hepatosplenic schistosomiasis. Once deposited into the lungs, the eggs elicit an immune response resulting in periovular granuloma formation. Immune mediators drive transforming growth factor-β (TGF-β) release, which gives rise to pulmonary vascular inflammation with subsequent remodeling and development of angiomatoid and plexiform lesions. These mechanisms elicited by the eggs seem to become autonomous and the vascular lesions progress independently of the antigen. Portopulmonary hypertension, which pathogenesis is still uncertain, may also play a role in the genesis of Sch-PAH. Recently, there have been substantial advances in the diagnosis and treatment of PAH, but it remains a difficult condition to recognize and manage, and patients still die prematurely from right-heart failure. Echocardiography is used for screening, and the formal diagnosis requires right-heart catheterization. The experience in treating Sch-PAH is largely limited to the phosphodiesterase type 5 inhibitors, with evidence suggesting that these vasodilators improve symptoms and may also improve survival. Considering the great deal of uncertainty about Sch-PAH pathogenesis, course, and treatment, the aim of this review is to summarize current knowledge on this condition emphasizing its pathogenesis.

Parasitic lung diseases

“…Current therapies for SchPAH rely on nitric oxide pathway inhibitors such as phosphodiesterase type 5 inhibitors (sildenafil and tadalafil), soluble guanylyl cyclase stimulators (riociguat), endothelian receptor antagonists (bosentan, ambrisentan and macitentan) and prostacyclin analogues (epoprostenol, treprostinil, iloprost, and the nonprostanoid IP-receptor agonist selexipag), as fully described by S ibomana et al [ 47 ]. Experience has shown that phosphodiesterase type 5 inhibitors improve symptoms and may also increase survival rates [ 48 ].…”

C-reactive protein and high-sensitivity C-reactive protein levels in asymptomatic intestinal parasite carriers from urban and rural areas of Gabon

“…For instance, some hookworms cause chronic iron-deficiency anemia; and iron deficiency has been reported to be associated with an increase in hsCRP or other inflammatory markers among healthy adults [28,29]. Through egg migration-induced inflammation, egg embolization, and granuloma development, Schistosoma species are causes of cancer, induce renal diseases or pulmonary hypertension which can cause right ventricular failure [30]. Heavy trichuriasis causes chronic infiltration of inflammatory cells in the colon of infected children as well as iron-deficiency anemia [31].…”

Experimental animal models of pulmonary hypertension: Development and challenges

“…Schistosome‐related PAH (Sch‐PAH) is a fatal complication of chronic schistosomiasis infection with unknown mechanism, and a leading cause of PAH‐related morbidity and mortality worldwide 54,55 . Current evidence suggests that mechanical obstruction of lung vasculature by embolized eggs, systemic inflammation, pulmonary vascular remodeling, and underlying liver disease might be the most relevant pathogenic mechanisms for Sch‐PAH 56 . Female C57/BL6 mice can develop severe vascular remodeling from 12 weeks onwards after transcutaneous injection with a low dose (approximately 30 cercariae) of Schistosoma mansoni , characterized by perivascular inflammation, marked medial thickening and the formation of plexiform‐like lesions without significant PH 57 .…”

“…54,55 Current evidence suggests that mechanical obstruction of lung vasculature by embolized eggs, systemic inflammation, pulmonary vascular remodeling, and underlying liver disease might be the most relevant pathogenic mechanisms for Sch-PAH. 56 Female C57/ BL6 mice can develop severe vascular remodeling from 12 weeks onwards after transcutaneous injection with a low dose (approximately 30 cercariae) of Schistosoma mansoni, characterized by perivascular inflammation, marked medial thickening and the formation of plexiform-like lesions without significant PH. 57 Female mice manifested a heavier worm burden than males during chronic infection, as the presence of testosterone results in decreased schistosome survival and increased host survival in experimental infections, and the extent of pulmonary vascular remodeling correlated with levels of inflammatory cytokines and lung egg burden.…”